Background

As a consequence of mutations in the genes encoding the LDL receptor (LDLR), apolipoprotein (apo) B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9), patients with familial hypercholesterolaemia (FH) have high plasma LDL-c concentrations and high cardiovascular (CV) risk [1,2].
Although statins have been shown to reduce LDL-c levels and increase life expectancy in patients with heterozygous FH (HeFH), most HeFH patients do not meet recommended LDL-c targets [3].
Cholesterol ester-transfer protein (CETP) inhibitors, like anacetrapib, limit transfer of cholesterol from HDL to LDL particles in plasma [4], which lowers the levels of cholesterol in atherogenic lipoproteins, while HDL-c and apo A1 concentrations increase [5].
The randomised evaluation of anacetrapib lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE) study assessed the safety and efficacy profile of anacetrapib 100 mg once daily in patients with HeFH, who were on optimum dose of statin and possibly on one or more other lipid-modifying drugs. Patients had a genotype-confirmed or a clinical diagnosis of HeFH. 204 patients were randomised to 52 weeks of treatment with anacetrapib 100 mg (174 completed the 52 weeks), and 102 to placebo (88 completed).

HDL-c and Apo A1 were significantly elevated with anacetrapib as compared with placebo. The HDL-c increasing effect was near-maximum within 6 weeks, and stable throughout the study.

Anacetrapib 100 mg was well tolerated, with the only significantly different safety variable being higher diastolic blood pressure in the placebo group. One non-fatal myocardial infarction and three episodes of unstable angina occurred in the anacetrapib group, but this difference was not statistically significant, as was the higher proportion of patients on anacetrapib with adverse events (AEs) leading to discontinuation.
An increased incidence of skin-related AEs was seen with anacetrapib as compared with placebo (19.203 (19%) vs. 2/102 (2%), P=0.0162).

Conclusion

Treatment with anacetrapib 100 mg once daily, in addition to optimal lipid-lowering treatment, lowered plasma concentrations of atherogenic lipoproteins in patients with heFH, while concentrations of particles with potential antiatherogenic properties were increased. More patients on anacetrapib reached LDL-c treatment targets than patients on placebo.
Anacetrapib was generally well-tolerated, and, importajntly, did not affect blood pressure.
The effect of CETP inhibition with anacetrapib on CV events needs further assessment in the better-powered REVEAL Study, evaluating anacetrapib in high-risk patients without FH.